Molecular mechanisms underlying ischemic neuronal death have been extensively investigated these twenty years. While several drugs such as glutamate receptor antagonists and free radical scavengers attracted much attention as potential neuroprotive agents, randomized clinical trials have failed to show any beneficial effect of those drugs for acute ischemic stroke patients. However, recent advance in molecular biology of NMDA receptor may explain why NMDA receptor antagonists were toxic rather than beneficial in ischemic stroke patients. NMDA receptors consisted of two subtypes, synaptic and extrasynaptic receptors. It is likely that activation of synaptic receptors results in survival while that of extrasynatpic ones causes cell death in cultured neuron. Antagonists specific to extrasynaptic receptor could be promising for neuroprotection. Hibernation and hypothermia both show robust protection against decreased levels of cerebral blood flow in experimental animals. Ischemic tolerance is well known phenomenon in that sublethal ischemic stress induces resistance of neurons against subsequent severe ischemic insult. Recent studies using cDNA microarray revealed that gene expression of cell metabolism and ion channel was down-regulated in tolerant brain. Metabolic downregulation would underlie the protective action of hibernation, hypothermia and ischemic tolerance. Therapeutic application of metabolic downregulation could be further investigated in next few years.
